The pathogenic role of D-2-hydroxyglutarate in cancers caused by isocitrate dehydrogenase mutations

Primary Supervisor: Prof Ian Tomlinson

Daily Supervisor: Chiara Bardella

Project Overview

Gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. Due to their locally aggressive behaviour and the fact that they cannot be cured by current therapies, these are one of the most devastating cancers. Many gliomas and other cancer types show mutations in a protein called IDH1.

Mutant IDH1 causes tumour initiation possibly through accumulation of a compound called D2-hydroxyglutarate (D2HG), which is usually a product of normal biochemical  processes in cells. It is thought that when D2HG accumulates in cells, it may cause dysregulation of various proteins, which then lead to cancer. Previously, we found that adult mice expressing mutant Idh1 in the brain developed various features of early glioma development. Unfortunately, new treatments designed to decrease D2HG seem to have limited efficacy on IDH-mutant gliomas raising the question of whether D2HG is critical to cause this type of cancer.

This project aims clarify the role of D2HG in IDH-mutant glioma cells. To understand the role of D2HG we will investigate and compare the cellular and molecular properties of IDH-mutant cancer cells before and after clearing excess D2HG. To achieve this, IDH mutant cells we will engineered to exogenously express the D2HGDH enzyme, which is responsible for the conversion of D2HG into αketoglutarate. A better understanding of the cellular and molecular events that affect glioma development driven by mutant IDH1 is critical to develop effective treatments.

Training Opportunities

The student will acquire skills in tissue and cell culture and will be trained in all aspects of:

• Development and study of mouse and cell models of cancer
• Molecular and metabolic profiling of cells and tissues
• Bioinformatics and biostatistics related to the project

References

1.  Bardella, C., Al-Dalahmah, O., Krell, D., Brazauskas, P., Al-Qahtani, K., Tomkova, M., Adam, J., Serres, S., Lockstone, H., Freeman-Mills, L. and Pfeffer, I., 2016. Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer cell, 30(4), pp.578-594. 
2. Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors. Reinbold R, Hvinden IC, Rabe P, Herold RA, Finch A, Wood J, Morgan M, Staudt M, Clifton IJ, Armstrong FA, McCullagh JSO, Redmond J, Bardella C, Abboud MI, Schofield CJ. Nat Commun. 2022 Aug 15;13(1):4785. doi: 10.1038/s41467-022-32436-4. PMID: 35970853 
3. Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis. Hollinshead KER, Munford H, Eales KL, Bardella C, Li C, Escribano-Gonzalez C, Thakker A, Nonnenmacher Y, Kluckova K, Jeeves M, Murren R, Cuozzo F, Ye D, Laurenti G, Zhu W, Hiller K, Hodson DJ, Hua W, Tomlinson IP, Ludwig C, Mao Y, Tennant DA. Cell Rep. 2018 Mar 20;22(12):3107-3114. doi: 10.1016/j.celrep.2018.02.084. PMID: 29562167